We have proposed the following Core Concept for this project: Restless Legs Syndrome (RLS) symptoms result from altered dopaminergic mechanisms that are precipitated by a relative or absolute reduction of iron in the brain. A major aim of this proposal is to integrate the activities of various disciplines such that the interrelationships will result in a greater scientific contribution than could be achieved if each project were pursued individually. The long-range goal of this Program Project is to confirm and better specify the relationship between brain iron insufficiency, DA abnormalities, and RLS;and also to determine the cause of the brain iron insufficiency in RLS and how it may relate to DA system abnormalities. This would hopefully lead to potential new treatments for RLS and possibly new approaches to understanding RLS and other disorders that involve brain iron dysregulation. The program has several important strengths: 1) Many of the principal investigators have a long history of interaction around the specific issue to be addressed in this Program: Iron and dopamine and their potential interaction and their roles in RLS. 2) Strong, new investigators are integrated into the Program. 3) Many of the investigators are leaders in the fields of brain iron metabolism, iron-dopamine interaction, human iron metabolism, Restless Legs Syndrome, PET techniques for assessment of the dopaminergic system, MRI quantification of iron, and QTL analysis using inbred strains of mice. 4) Investigators will use sophisticated PET, MRI, neuropathological, biological, and mice inbreeding approaches that have been incorporated to facilitate novel insights into the interaction of iron, dopamine and their relevance to RLS.